Natural products provide a wide range of biologically active agents, many of which have unique profiles of pharmacological activity and therapeutic potential. Over five hundred alkaloids have been identified in extracts from amphibian skins. These include batrachotoxins, which are potent activators of sodium channels, histrionicotoxins, which are noncompetitive blockers of nicotinic receptor-channels and potassium channels, pumiliotoxins/allopumiliotoxins and related homopumiliotoxins, which have myotonic and cardiotonic activity due to effects on sodium channels, and epibatidine, an extremely potent and selective nicotinic agonist with potent antinociceptive activity. Further alkaloids include 2,5-disubstituted decahydroquinolines, 3,5- disubstituted pyrrolizidines, 3,5-disubstituted, 5,8-disubstituted and 5,6,8-trisubstituted indolizidines,1,4-disubstituted and 4,6- disubstituted quinolizidines, an unique class of 3,5-disubstituted homoindolizidines (azabicyclo[5.3.0]decanes), and a variety of tricyclic alkaloids,including pyrrolizidine oximes, gephyrotoxins, pseudophrynamines, cyclopentaquinolizidines, coccinellines and coccinelline analogs. Many of these are noncompetitive blockers of nicotinic receptor channels; some are selective and others nonselective. Most of the five hundred alkaloids have been detected and characterized from skin of neotropical dendrobatid frogs. Lipophilic alkaloids also occur in skins from one genus of Australian myobatrachid frogs, one genus of South American bufonid toads and one genus of Madagascan mantelline frogs. With one exception, it appears frog skin alkaloids have a dietary origin, being taken up and sequestered unchanged into skin glands. The uptake system appears highly conserved for three of the four family groups that contain skin alkaloids, at least with respect to alkaloid substrates. It has now been discovered that pseudophrynamines, a class of indolic alkaloids found only in frogs of the Australian genus Pseudophryne, are produced by the frogs themselves, while the uptake system is selective for pumiliotoxins/allopumiliotoxins, the only other class of alkaloids found in skin of these frogs. Ants, beetles and millipedes have been found to be the source of certain frog skin alkaloids,representing a total of eight structural classes. The origin of the batrachotoxins, histrionicotoxins, pumiliotoxins, homopumiliotoxins, epibatidines and the remaining eight other structural classes found in frog skin remains a mystery. Histrionicotoxins, gephyrotoxins, and the homoindolizidines will probably be of ant origin. Batrachotoxins are present in feathers and skin of some, but not all populations of several species of passerine birds of the genus Pitohui that occur in Papua New Guinea. Batrachotoxins have now been found in skin and feathers of another New Guinean bird of an unrelated passcrine genus Ifrita. Several previously unknown batrachotoxins have been discovered in both Pitohui and Ifrita birds. Whether the birds also are dependent on a dietary source for batrachotoxins is unknown. A unusual alkaloid present in muscle, which appears to protect such birds from the highly toxic batrachotoxins, has been characterized but a tentative structure must be confirmed by synthesis. Structures have now been determined for a 4,6-disubstituted quinolizidine, an unusual 5,6,8-trisubstituted indolizidine containing a branched side chain, an oxirane-containing allopumiliotoxin and a homoindolizidine. Absolute stereochemistry of several alkaloids have been determined by chiral chromatographic comparison with synthetic standards. A peptide in skin extracts from a hylid frog that inhibits the binding of glibenclamide to ATP-dependent potassium channels is has been defined, but it now appears that PLA(2) activity of the peptide (mw 4737) confers activity. Other peptides that affect adenosine binding are under investigation. A CI/MS collision activated mass spectrometric technique has been developed and is being used to obtain and intepret fragmentations entirely different than the radical fragmentations obtained from EI spectra. The data has already defined one new alkaloid class and provide definitive evidence for another.